Making decisions about hormone replacement therapy

All rapid responses

Rapid responses are electronic letters to the editor. They enable our users to debate issues raised in articles published on thebmj.com. Although a selection of rapid responses will be included online and in print as readers' letters, their first appearance online means that they are published articles. If you need the url (web address) of an individual response, perhaps for citation purposes, simply click on the response headline and copy the url from the browser window. Letters are indexed in PubMed.

The recent publication of results from the Women's Health Initiative
(1) introduced a new dimension into decisions regarding the risks and
benefits of Hormone Replacement Therapy (HRT), causing concern and
uncertainty amongst doctors and patients alike. I was thus delighted to
come across a Clinical Review in the BMJ which set out to 'define who
should be offered hormone replacement therapy and why...and clarify the
advantages and disadvantages of treatment'.(2)

My initial sense of anticipation rapidly waned as I read the article,
the authors' evident enthusiasm for HRT making it difficult to accept the
objectivity of their conclusions. For instance: 'Hormone replacement
therapy seems to be associated with an increased risk of breast cancer,
myocardial infarction, cerebrovascular disease, and thromboembolic
disease'. Surely these risks are by now well established and not a matter
for debate. 'Hormone replacement therapy may...be unmasking an underlying
thrombophilic tendency'. Is there any evidence for this hypothesis? 'The
results of these studies (HERS, WHI) cannot be extrapolatd to other
forms...of hormone replacement therapy since different progestogens have
significantly different effects'. Is it not reasonable (and prudent) to
assume, until there is evidence to the contrary, that these are in fact
class effects?

The relentlessly pro-HRT tone of this paper made it read like
something I would have expected to be handed by a pharmaceutical company
representative rather than find in the pages of a respected peer-reviewed
journal. Might I suggest that in future any such subjective review be
balanced by another giving an alternative viewpoint. Better still, why not
stick to systematic reviews, whose rigorous approach is more likely to
lead to a definitive presentation of the best evidence at that point in
time.

They are less clear about the absolute benefits of HRT, preferring to
point out only that the WHI trial achieved what so many other trials had
failed to do: it demonstrated a reduction in the risk of hip fracture from
HRT.

The magnitude of that risk reduction is small. The WHI investigators
found that HRT reduced the absolute risk of hip fracture from 15/10,000
years to 10/10,000 years. Vertebral fractures were reduced from 15/10,000
years to 9/10,000 years and "other osteoporotic" fractures from 169/10,000
years to 131/10,000 years, an absolute reduction of 38/10,000 years. In
this age group (mean age 63.2 years) the majority of the "other" fractures
are likely to have been wrist fractures.

Overall, these are small risks - 1 in 62 women will be harmed by 5
years of treatment. But the benefit is smaller still - 1 in 180 women
avoid a hip fracture or colonic tumour after 5 years treatment. If the
higher rate of "other fractures" is taken into account, the absolute
benefit rises to 1 in 40 women, but note many of these fractures are
likely to be relatively minor.

There are problems with generalising from the WHI data to a British
population. Our population is likely to be younger, and hence the absolute
risks of heart disease, fracture and cancer all lower. This will attenuate
the risks, but also any benefit of HRT; the overall risk/benefit ratio is
likely to remain weighted against treatment, and the financial costs of
achieving any benefit will rise. The formulation used in the WHI trial is
different from any used in the UK - but no evidence exists that other
formulations are safer or more effective. Observational studies show
benefit in cardiac disease, lipid profiles and other secondary measures;
but WHI is a well conducted, large RCT. The dogma of EBM teaches us it far
outweighs small-scale observational reports of secondary outcomes.

There are other therapeutic options for osteoporosis. Bisphosphonates
reduce the risk of hip and other fractures; raloxifene reduces the risk of
vertebral fractures and breast cancer. Bisphosphonates have no cardiac
adverse effects (or others, that we know of). The RUTH trial is currently
studying whether raloxifene is beneficial or harmful from a cardiac
perspective, but data from the MORE trial (3) indicates no effect either
way. Whether these drugs are efficacious enough in the immediate
postmenopausal setting (where the absolute risk of fracture is still quite
low) to justify their long term costs awaits a better pharmacoeconomic
model of osteoporosis.

Long term use of HRT in early menopause, and short term use in women
with vasomotor symptoms are the only remaining indications left for HRT.
Rymer et al are clinging to old habits in recommending HRT should be
offered to postmenopausal women at risk of osteoporosis. The tide of the
evidence is against them, and it is time to sit up and take notice, as our
American colleagues are doing (4).

We read with interest the clincal review "Making decisions about
hormone replacement therapy". The article provides a usful and informed
guide to the indications for hormone replacement (HRT) and a helpful
analysis of the risks and benefits.

We take issue however with one important point. As a surgical
oncology team specialising in the treatment of breast cancer we feel it
important to point out that the theraputic value of gonadotrophin
releasing hormone (GHRH) analogues in the treatment of breast cancer is
based on their surpression of ovarian function and the consequent
reduction in the levels of circulating oestrogen in women whose tumours
are oestrogen receptor (ER) positive. In these women oestrogen containing
preparations should not be used since their use will compromise the value
and efficacy of treatment for breast cancer.

The use of HRT in women who have been treated at some time in the
past for breast cancer may well be safe but it should
not be used concurrently with treatments aimed at ovarian surpression.

I am surprised to see that the authors of this review recommend
giving HRT to women who have temporary ovarian failure as a result of
treatment with gonadotrophin releasing hormone analogues(for example,
women with breast cancer). HRT may well prevent bone loss, but if the GnRH
analogue is being used to suppress ovarian function in women with
oestrogen receptor positive breast cancer then surely the risks are too
great?

An increasing number of women have had endometrial ablation for
control of menorrhagia. In the past many or all of these women would have
had hysterectomy. What is the correct management of these women once they
are memopausal?
If they need oestrogen is it necessary to give them progesterone or will
it increase their risk of morbidity to a greater extent than it will
reduce it. In other words if the endometrium has been ablated but there is
still a uterus is there an obligation to give combined HRT?

Added benifits of HRT (horomone replacement therapy) that are
readily visible in parients followed for many years are the maintaning of
skin quality, in terms of skin thickness and subcuticular elastic
tissue.The fraility of the skin and the ability to get large skin tears
after very minor trauma limits the activity of many older women. This
group of patients also have muscle atrophy that limits activity by extream
fatiquabilty and also contributes to frequent falls. The above leads to a
reduced quality of life for many, and I think should be taken into account
when discussing the benifits of HRT.

EDITOR- Janice Rymer et al’s advice about the use of hormone
replacement therapy (HRT)1 is at odds with the advice of Fletcher and
Colditz.2 In the JAMA Editorial which accompanied the prematurely
terminated Women’s Health Initiative (WHI) Study, they wrote, “do not use
estrogen /progestin to prevent chronic disease”.

Immunosuppressive, carcinogenic sex hormones never have been the
correct treatment for menopausal symptoms or osteoporosis. In reality,
vascular over-reactivity responds safely to the removal of major
precipitants like oral contraceptives (OCs) and HRT, drugs, tobacco and
alcohol.3 Use of progestogen dominant formulations causes vaginal dryness
and soreness, even in young women. As exogenous hormone use can cause
zinc, magnesium, B vitamins, folic acid and essential fatty acid
deficiencies, such use increases the risk of diseases, including
osteoporosis and menopausal symptoms. McLaren-Howard et al 4 and Villareal
et al 5 found that HRT caused marked reductions in serum bone specific-
alkaline phosphatase, which is an index of bone formation. Osteoporotic
women also have low white blood cell zinc and low red blood cell magnesium
concentrations and these are significantly lower if they are taking HRT.
It is important to stop HRT to allow repletion of zinc and magnesium
deficiencies and increases in serum bone-specific alkaline phosphatase
levels.4

The idea that hormones can increase risks of breast, cervical,
endometrial, ovarian, lung, liver and skin cancers, but not colorectal
cancer, is absurd. Most women randomised to take placebos in relatively
short controlled trials already have higher risks of cancer because nearly
all have used oestrogens and progestogens. Varying lengths of previous
exposures, including past OC use, are not usually taken into account.
Underestimations could explain unlikely results, such as reduced risk of
fractures, colorectal or endometrial cancers, in placebo groups. Too many
women doctors, often to their personal cost, have believed scientifically
invalid claims of benefit.

Many people, including the authors of this review, suggest that
bisphosphonates can be used instead of estrogen for the
prevention of osteoporotic fractures. Clinical trials of
bisphosphonates in peri-menopausal women have shown a
stabilization of bone density, but no difference in fracture rate
compared to a placebo. The only studies that have shown a
significant reduction in fractures with bisphosphonates have been
in women who are older and already have osteoporosis. There
have been many observational studies showing lower fracture
rates in women who used estrogen for 10 to 20 years. These data
do not exist for bisphosphonates. The long-term (greater than 10
years) use of bisphosphonates might be beneficial, but they
possibly could make the bone more brittle due to the profound
suppression of bone formation rates.

We should not recommend
that women aged 50 to take bisphosphonates for prevention of
fractures that are unlikely to occur before age 70 until we have
data that these drugs are effective at preventing fractures 20 years
in the future.